De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis

Mariely DeJesus-Hernandez, Jannet Kocerha, Nicole Finch, Richard Crook, Matt Baker, Pamela Desaro, Amelia Johnston, Nicola Rutherford, Aleksandra Wojtas, Kathleen Kennelly, Zbigniew K. Wszolek, Neill Graff-Radford, Kevin Boylan, Rosa Rademakers

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS mutation (g.10747A>G; IVS13-2A>G) affects the splice-acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C-terminal truncation of FUS (p.G466VfsX14). Subcellular localization studies showed a dramatic increase in the cytoplasmic localization of FUS and a reduction of normal nuclear expression in cells transfected with truncated compared to wild-type FUS. We further identified a novel in-frame insertion/deletion mutation in FUS exon 12 (p.S402-P411delinsGGGG) which is predicted to expand a conserved poly-glycine motif. Our findings extend the mutation spectrum in FUS leading to ALS and describe the first de novo mutation in FUS.

Original languageEnglish (US)
Pages (from-to)E1377-E1389
JournalHuman mutation
Volume31
Issue number5
DOIs
StatePublished - May 1 2010

Keywords

  • Amyotrophic lateral sclerosis
  • De novo mutation
  • FUS splice-site mutation
  • FUS truncating mutation
  • FUS/TLS
  • Fused in sarcoma

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    DeJesus-Hernandez, M., Kocerha, J., Finch, N., Crook, R., Baker, M., Desaro, P., Johnston, A., Rutherford, N., Wojtas, A., Kennelly, K., Wszolek, Z. K., Graff-Radford, N., Boylan, K., & Rademakers, R. (2010). De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis. Human mutation, 31(5), E1377-E1389. https://doi.org/10.1002/humu.21241